Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion

Zenan Wang, Binghao Li, Shan Li, Wenlong Lin, Zhan Wang, Shengdong Wang, Weida Chen, Wei Shi, Tao Chen, Hao Zhou, Eloy Yinwang, Wenkan Zhang, Haochen Mou, Xupeng Chai, Jiahao Zhang, Zhimin Lu and Zhaoming Ye ()
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Zenan Wang: Zhejiang University School of Medicine
Binghao Li: Zhejiang University School of Medicine
Shan Li: Zhejiang University School of Medicine
Wenlong Lin: Zhejiang University School of Medicine
Zhan Wang: Zhejiang University School of Medicine
Shengdong Wang: Zhejiang University School of Medicine
Weida Chen: Zhejiang University School of Medicine
Wei Shi: Zhejiang University School of Medicine
Tao Chen: Zhejiang University School of Medicine
Hao Zhou: Zhejiang University School of Medicine
Eloy Yinwang: Zhejiang University School of Medicine
Wenkan Zhang: Zhejiang University School of Medicine
Haochen Mou: Zhejiang University School of Medicine
Xupeng Chai: Zhejiang University School of Medicine
Jiahao Zhang: Zhejiang University School of Medicine
Zhimin Lu: Zhejiang University School of Medicine
Zhaoming Ye: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.

Date: 2022
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DOI: 10.1038/s41467-022-34064-4

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